ABCMdb

PMID: 25443471

Marion H, Natacha G, Brigitte M, Francois C, Michel R, Corinne T, Emmanuelle G, Thierry B
The p.Gly622Asp (G622D) mutation, frequently found in Reunion Island and in black populations, is associated with a wide spectrum of CF and CFTR-RD phenotypes.
J Cyst Fibros. 2015 May;14(3):305-9. doi: 10.1016/j.jcf.2014.11.001. Epub 2014 Nov 28., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCC7 p.Gly622Asp ABCC7 p.Gly622Asp Original Article The p.Gly622Asp (G622D) mutation, frequently found in Reunion Island and in black populations, is associated with a wide spectrum of CF and CFTR-RD phenotypes Heller Marion a , Gaitch Natacha a , Martinez Brigitte a , Cartault Fran&#e7;ois b , Renouil Michel b , Theze Corinne c , Girodon Emmanuelle a , Bienvenu Thierry a,d,Ìe; a AP-HP, Laboratoire de Biochimie et G&#e9;n&#e9;tique Mol&#e9;culaire, GH Cochin-Broca-H&#f4;tel Dieu, Paris, France b Service de G&#e9;n&#e9;tique, Centre Hospitalier Saint Denis, Saint Denis, La R&#e9;union, France c Laboratoire de G&#e9;n&#e9;tique Mol&#e9;culaire, IURC, Institut Universitaire de Recherche Clinique, 34093 Montpellier Cedex 5, France d Universit&#e9; Paris Descartes Paris, Institut Cochin, INSERM U1016, Paris, France Received 2 July 2014; revised 14 October 2014; accepted 2 November 2014 Available online 28 November 2014 Abstract Examination of genotype-phenotype correlations along with functional evaluation of CFTR mutations may not be straightforward. Login to comment 1 ABCC7 p.Gly622Asp ABCC7 p.Gly622Asp The c.1865G N A, p.Gly622Asp (G622D), located at the NBD1 C terminus of the CFTR protein, was initially reported in patients with male infertility. Login to comment 2 ABCC7 p.Gly622Asp However, the substitution of Gly622 by an aspartic acid in vitro would perturb the local structure or even affect the CFTR folding itself. Login to comment 3 ABCC7 p.Gly622Asp ABCC7 p.Gly622Asp In order to determine whether p.Gly622Asp affects the risk of developing a CFTR-Related disorder (CFTR-RD) or cystic fibrosis (CF), we analyzed the phenotype of subjects bearing the p.Gly622Asp mutation. Login to comment 4 ABCC7 p.Gly622Asp We report molecular and clinical analyses in eleven unrelated patients with CF or CFTR-RD with compound heterozygosity for the p.Gly622Asp mutation. Login to comment 5 ABCC7 p.Gly622Asp On the basis of the clinical features presented by the eleven patients, we postulate that the p.Gly622Asp might be associated with a wide spectrum of phenotypes including classical cystic fibrosis. Login to comment 12 ABCC7 p.Gly622Asp ABCC7 p.Gly622Asp ABCC7 p.Gly628Arg ABCC7 p.Gly628Arg Two nucleotide substitutions were reported in the CFTR gene (NM_000492.3) at position 628 giving rise to p.Gly628Arg (G628R) in CF patients, c.1882G N A and c.1882G N C, while one mutation has been described at position 622, c.1865G N A, p.Gly622Asp (G622D), reported in 1998 by Zielenski et al. in a patient with oligospermia (http:// www.genet.sickkids.on.ca/cftr/) [1]. Login to comment 13 ABCC7 p.Gly622Asp p.Gly622Asp was further reported at a 0.18% allelic frequency among African Americans in a carrier screening program [2]. Login to comment 14 ABCC7 p.Gly622Asp In 1998, Vankerberghen et al. evaluated the impact of this missense change on the channel behavior and found that p.Gly622Asp did not affect chloride transport ability but gave rise to a CFTR chloride channel with Ìe; Corresponding author at: Laboratoire de Biochimie et G&#e9;n&#e9;tique Mol&#e9;culaire, H&#f4;pital Cochin, 27 rue du Faubourg Saint Jacques, 75014 Paris, France. Login to comment 19 ABCC7 p.Gly622Asp These functional data suggested p.Gly622Asp as a possible CFTR-related disorder (CFTR-RD) associated mutation. Login to comment 20 ABCC7 p.Gly622Asp Ten years later, Norez et al. showed that p.Gly622Asp-expressing COS7 cells have a reduced transport activity compared with wild-type CFTR cells and a partial trafficking defect that can be reversed by misglustat [3]. Login to comment 21 ABCC7 p.Gly622Asp Recently, Billet et al. expressed mutant and WT CFTR in HEK 293 cells and detected no mature-glycosylated C-band for the mutant and a significant reduced current density, suggesting that the substitution of Gly622 by an aspartic acid would perturb the local structure or even affect the folding itself [4]. Login to comment 22 ABCC7 p.Gly622Asp ABCC7 p.Gly622Asp To unravel discrepancies between these previous reports, and in order to determine whether or not p.Gly622Asp affects the risk of developing a CFTR-RD or CF, we analyzed the phenotype of subjects bearing the p.Gly622Asp mutation. Login to comment 34 ABCC7 p.Tyr122* ABCC7 p.Gly622Asp ABCC7 p.Gly622Asp For patients, healthy individuals and fetuses originating for Reunion Island (903 samples in total), a systematic search for c.366T N A, p.Tyr122Ter (Y122X) and c.1865G N A, p.Gly622Asp (G622D) was performed because of their particular occurrence in this population. Login to comment 44 ABCC7 p.Gly622Asp Results We identified a total of 24 carriers of the p.Gly622Asp mutation among 903 individuals from Reunion Island. Login to comment 49 ABCC7 p.Tyr122* All carried on the other allele a severe CF-causing mutation such as c.366T N A, p.Tyr122Ter (Y122X), n = 3, and c.2988 + 1G N A (3120 + 1G N A), n = 1 (Table 3). Login to comment 51 ABCC7 p.Gly622Asp In particular, none of the four patients carried the c.3717 + 45G N A (3849 + 45G N A) variation, which was already reported in cis with p.Gly622Asp. Login to comment 52 ABCC7 p.Gly622Asp p.Gly622Asp was also found in eight infertile males, five with azoospermia and three with oligoasthenozoospermia (from 0.2 to 7 M spermatozoa/ml). Login to comment 53 ABCC7 p.Gly622Asp Four of them were compound heterozygous: three Table 1 Frequency of the p.Gly622Asp missense mutation in different groups of subjects from Reunion Island. Login to comment 54 ABCC7 p.Gly622Asp Phenotype Number of individuals p.Gly622Asp carriers (number) Allele frequency (%) Cystic fibrosis (suspected or established) 56 6 5.35 Echogenic bowel 183 7 1.91 Male infertility 222 8 1.80 Idiopathic bronchiectasis 15 0 0.0 Idiopathic pancreatitis 15 0 0.0 Unaffected individuals 412 3 0.36 carried a severe CF mutation (c.1521_1523del (F508del), c.2988 + 1G N A) and one a CFTR-RD mutation (c.1210-12T [5]). Login to comment 56 ABCC7 p.Gly622Asp ABCC7 p.Lys951Gln ABCC7 p.Lys951Glu p.Gly622Asp was also detected in three fetuses who were studied because of hyperechogenic bowel and were found to carry a CFTR-RD variant such as c.2851A N G, p.Lys951Gln (K951E), c.1210-12T[5] and c.1584G N A (1716G N A) (Table 3). Login to comment 60 ABCC7 p.Gly622Asp Because the CFTR genetic background could influence the potential pathogenicity of the p.Gly622Asp mutation, we studied the haplotype background. Login to comment 61 ABCC7 p.Gly622Asp Three intragenic CFTR microsatellites, c.53 + 10167CA(17_26) (IVS1CA), c.1210-307GT(16_24) (IVS8CA) and c.3367 + 200TA(7_56) (IVS17bCA), were typed for seven p.Gly622Asp heterozygotes. Login to comment 63 ABCC7 p.Gly622Asp We also studied the association of p.Gly622Asp with the c.1408A N G, p.Val470 allele in exon 11 and the c.1210-12T(5_9) (Tn repeat) located in intron 9 (traditional nomenclature), and with other variants in the CFTR gene. Login to comment 64 ABCC7 p.Gly622Asp We focused our analysis on the 11 compound heterozygotes showing Table 2 Clinical presentations of four cystic fibrosis cases with p.Gly622Asp mutation. Login to comment 67 ABCC7 p.Gly622Asp [Tyr122Ter];[Gly622Asp] p. Login to comment 68 ABCC7 p.Gly622Asp [Tyr122Ter];[Gly622Asp] p. Login to comment 69 ABCC7 p.Gly622Asp [Tyr122Ter];[Gly622Asp] c. Login to comment 70 ABCC7 p.Gly622Asp [2988 + 1G N A];[1865G N A] Phenotype CF CF CF CF Sweat Cl- (mEq/L) 78 63 80 63 Diabetes No No No No Cirrhosis No No No No Glucose intolerance No No No Yes (12 y) Nasal polyposis No No No No Intestinal disorders No No No No Pancreatic function PS PI (10 y) PI (4 y) PS FEV1(%) 85% 76% 99% 93% FVC (%) 79% 76% 86% 106% Pseudomonas aeruginosa No No Yes (3 y) No Staphylococcus aureus Yes (6 y) Yes (7 y) Yes (3 y) No Aspergillus fumigatus No Yes (6 y) No No Streptococcus pneumoniae No No No Yes (10 y) Haemophilus influenzae No Yes (4 y) Yes (4 y) Yes (10 y) Treatment PERT PERT PERT, steroid therapy PERT, steroid therapy, bronchodilatators Table 3 CFTR genotype and CFTR haplotype in subjects bearing the p.Gly622Asp mutation. Login to comment 74 ABCC7 p.Gly622Asp ABCC7 p.Gly622Asp ABCC7 p.Gly622Asp ABCC7 p.Gly622Asp ABCC7 p.Gly622Asp ABCC7 p.Gly622Asp ABCC7 p.Gly622Asp ABCC7 p.Gly622Asp ABCC7 p.Gly622Asp ABCC7 p.Gly622Asp ABCC7 p.Gly622Asp ABCC7 p.Lys951Glu Mutation 1 Mutation 2 5/7/9T allelea TG repeatb Codon 470 c.3717 + 45G N A Codon 854 5'UTR Patients with cystic fibrosis MUC821 p.Gly622Asp p.Tyr122Ter T7;T7 nd VV No c.2562T N G homo c.-8G N C MUC822 p.Gly622Asp p.Tyr122Ter T7;T7 nd VV No c.2562T N G homo c.-8G N C MUC940 p.Gly622Asp p.Tyr122Ter T7;T7 nd VV No No c.-8G N C R156C p.Gly622Asp c.2988 + 1G N A T7;T7 nd MV No c.2562T N G No Patients with male infertility MUC2815 p.Gly622Asp c.2988 + 1G N A T7;T7 nd nd No nd No MUC3913 p.Gly622Asp p.Phe508del T7;T9 nd MV No No No MUC4216 p.Gly622Asp p.Phe508del T7;T9 nd MV Yes No No MUC4811 p.Gly622Asp c.1210-12T[5] T5;T7 TG11;TG12 VV No No No Fetuses with hyperechogenic bowel MUC5131 p.Gly622Asp c.1210-12T[5] T5;T7 TG11;TG12 MV Yes c.2562T N G No MUC6775 p.Gly622Asp p.Lys951Glu T7;T7 nd MV No c.2562T N G No MUC4196 p.Gly622Asp c.1584G N A T7;T7 nd nd No nd No a c.1210-12T(5_9). Login to comment 77 ABCC7 p.Gly622Asp We found that the p.Gly622Asp was associated with the p.Val470 allele in all informative cases (4/4) (Table 3). Login to comment 79 ABCC7 p.Gly622Asp We found that the p.Gly622Asp was associated with the c.1210-12T[7] allele in all informative cases (6/6) (Table 3). Login to comment 81 ABCC7 p.Gly622Asp p.Gly622Asp was associated with the c. Login to comment 83 ABCC7 p.Gly622Asp Our findings showed no evidence of a difference in the distribution of the c.1210-12T(5_9) alleles and in the frequency of p.Met470Val variant between the different groups of subjects who carried the p.Gly622Asp variant. Login to comment 85 ABCC7 p.Gly622Asp Discussion c.1865G N A, p.Gly622Asp appears to be the second most common mutation after c.1521_1523del, p.Phe508del, in the African American general population, found at an allelic frequency of 0.18% (3/118 healthy individuals) while its worldwide allelic frequency is much lower, 0.05% (4/4088 healthy individuals) [2]. Login to comment 86 ABCC7 p.Gly622Asp Observations of p.Gly622Asp in patients are scarce. Login to comment 89 ABCC7 p.Gly622Asp Although several other studies have examined CF mutations in African Americans and African patients with a clinical diagnosis of CF, no individual bearing p.Gly622Asp was identified [5-8]. Login to comment 92 ABCC7 p.Gly622Asp Interestingly, we identified a total of 24 carriers of the p.Gly622Asp mutation among 903 individuals from Reunion Island. Login to comment 96 ABCC7 p.Gly622Asp Although p.Gly622Asp may be associated in cis with the c.3717 + 45G N A variant, which is considered as neutral, we could not identify a specific haplotype assigned to a CF-causing mutation or a CFTR-RD mutation. Login to comment 97 ABCC7 p.Gly622Asp ABCC7 p.Gly622Asp Although the existence of an undetected mutation in cis with p.Gly622Asp, possibly deep-intronic or located in regulatory regions, cannot be ruled out, it is cautious to consider p.Gly622Asp as a CF mutation. Login to comment 99 ABCC7 p.Leu206Trp ABCC7 p.Leu206Trp ABCC7 p.Asp1152His ABCC7 p.Asp1152His Other CFTR mutations have been associated with a large spectrum of phenotypes, such as c.3454G N C, p.Asp1152His (D1152H), c.617T N G, p.Leu206Trp (L206W), c.579 + 3A N G (621 + 3A N G). Login to comment 102 ABCC7 p.Gly622Asp However, it seems that the CF phenotype observed in patients carrying p.Gly622Asp may be more severe, thus making genetic counseling difficult. Login to comment 103 ABCC7 p.Gly622Asp Other authors suggested that, taking account the ethnic/ racial background of individuals, p.Gly622Asp should be included in the American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics (ACMG) CF mutation panel [2], especially with the development of specific CF assays using the next-generating sequencing technology. Login to comment 104 ABCC7 p.Gly622Asp As long as no clear explanation to such extreme phenotypes associated with p.Gly622Asp is found, our results support the recommendation of considering a CF allele whenever p.Gy622Asp is identified and of including it in future CF mutation screening panels, possibly targeted to individuals of African origin. Login to comment